1. Field of the Invention
The present invention relates to topical ophthalmic formulations used for treating allergic eye diseases, such as allergic conjunctivitis, vernal conjunctivitis, vernal keratoconjunctivitis, and giant papillary conjunctivitis. More particularly, the present invention relates to therapeutic and prophylactic topical use of 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid for treating and/or preventing allergic eye diseases.
2. Description of the Related Art
As taught in U.S. Pat. Nos. 4,871,865 and 4,923,892, both assigned to Burroughs Wellcome Co. ("the Burroughs Wellcome Patents"), certain carboxylic acid derivatives of doxepin, including 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepine-2-carboxyli c acid and 11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepine-2(E)-acryli c acid, have antihistamine and antiasthmatic activity. These two patents classify the carboxylic acid derivatives of doxepin as mast cell stabilizers with antihistaminic action because they are believed to inhibit the release of autacoids (i.e., histamine, serotonin, and the like) from mast cells and to inhibit directly histamine's effects on target tissues. The Burroughs Wellcome Patents teach various pharmaceutical formulations containing the carboxylic acid derivatives of doxepin; Example 8 (I) in both of the patents discloses an ophthalmic solution formulation.
Although both of the Burroughs Wellcome Patents claim that the variety of pharmaceutical formulations disclosed are effective both for veterinary and for human medical use, neither patent contains an example demonstrating that the carboxylic acid derivatives of doxepin have activity in humans. Example 7 in the Burroughs Wellcome Patents demonstrates antihistamine activity in male guinea pigs and Example G demonstrates anaphylactoid activity in Wistar rats.
It is now well established, however, that the types of mast cells which exist in rodents are different from those in humans. See, for example, THE LUNG: Scientific Foundations, Raven Press, Ltd., New York, Ch. 3.4.11 (1991). Moreover, mast cell populations exist within the same species that differ in phenotype, biochemical properties, functional and pharmacological responses and ontogeny. These recognized differences in mast cells both between and within species are referred to as mast cell heterogeneity. See for example, Irani et al., "Mast Cell Heterogeneity," Clinical and Experimental Allergy, Vol. 19, pp. 143-155 (1989). Because different mast cells exhibit different responses to pharmacological agents, it is not obvious that compounds claimed to be anti-allergic ("mast cell stabilizers") will have clinical utility in specific mast cell populations. The assumption that mast cells are a homogeneous population and that therefore the effects of anti-allergic drugs observed in experiments in rat mast cells would be predictive of those in human cells is known to be incorrect. Church, "Is Inhibition of Mast Cell Mediator Release Relevant to the Clinical Activity of Anti-Allergic Drugs?," Agents and Actions, Vol. 18, 3/4, 288-293, at 291 (1986).
Examples exist in the art in which mast cell stabilizing drugs inhibit only select populations of mast cells. Disodium cromoglycate is an anti-allergic drug whose local effects are believed to be due to inhibition of mast cell degranulation (Church, Agents and Actions, at 288). This drug was shown to inhibit rodent mast cell degranulation. In human trials, 100 .mu.M of the drug inhibited mast cells obtained from bronchoalveolar lavage fluid. In dispersed human lung mast cell preparations, 1000 .mu.M of the drug was required to inhibit only 25% to 33% of histamine release. Finally, histamine release from human skin mast cells was not inhibited at all by disodium cromoglycate. Pearce et al., "Effect of Disodium Cromoglycate on Antigen Evoked Histamine Release in Human Skin," Clinical Exp. Immunol., Vol. 17, 437-440 (1974); and Clegg et al., "Histamine Secretion from Human Skin Slices Induced by Anti-IgE and Artificial Secretagogues and the Effects of Sodium Cromoglycate and Salbutanol," Clin. Allergy, Vol. 15, 321-328 (1985). These data clearly indicate that classification of a drug as an anti-allergic does not predict that the drug possess inhibitory effects on all mast cell populations.
Topical ophthalmic formulations which contain drugs having conjunctival mast cell activity may only need to be applied once every 12-24 hours instead of once every 2-4 hours. One disadvantage to the ophthalmic use of reported anti-allergic drugs which in fact have no human conjunctival mast cell stabilizing activity is an increased dosage frequency. Because the effectiveness of ophthalmic formulations containing drugs which do not have conjunctival mast cell activity stems primarily from a placebo effect, more frequent doses are typically required than for drugs which do exhibit conjunctival mast cell activity.
U.S. Pat. No. 5,116,863, assigned to Kyowa Hakko Kogyo Co., Ltd., ("the Kyowa patent"), teaches that acetic acid derivatives of doxepin and, in particular, the cis form of the compound having the formula ##STR1## (i.e., Z-11-(3-dimethylaminopropylidene)-6,11-dihydrodibenz[b,e]oxepin-2-acetic acid), have anti-allergic and anti-inflammatory activity.
The Kyowa patent demonstrates anti-allergic activity and anti-inflammatory activity in Wistar male rats. Medicament forms taught by the Kyowa patent for the acetic acid derivatives of doxepin include a wide range of acceptable carriers; however, only oral and injection administration forms are mentioned. In the treatment of allergic eye disease, such as allergic conjunctivitis, such administration methods require large doses of medicine.
What is needed are topically administrable drug compounds which have demonstrated stabilizing activity on mast cells obtained from human conjunctiva, the target cells for treating allergic eye diseases. What is also needed are local administration methods for the treatment of allergic eye disease.